Risk Factors and Outcome of Chronic GVHD: Analysis of 5,660 Patients Undergoing Unrelated Bone Marrow Transplantation through the Japan Marrow Donor Program.

Abstract Background: Chronic GVHD (cGVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. However, there are limited data available on cGVHD after unrelated BMT (UR-BMT). We retrospectively analyzed the data of 5,660 patients who underwent UR-BMT through the Japan Marrow Donor Program (JMDP) between January 1993 and June 2004. Methods: Data were collected by the JMDP using a standard report form. Follow-up reports were submitted at 100 days, 1 year, and then annually after transplantation. Overall survival (OS) was estimated by the Kaplan-Meier method and patients surviving beyond day 100 after transplant were analyzed for the development of cGVHD. The log-rank test was used for univariate analysis and time-dependent Cox proportional hazards modeling was used for multivariate analysis. The cumulative incidence of cGVHD and of relapse was calculated using the Gray method considering death without cGVHD and death without relapse as respective competing risks. Results: The median age of all patients was 28 years and the median follow-up was 433.5 days after transplant. Estimated 5-year OS of all patients and those with hematological malignancies was 47.4% and 45.5%, respectively. A total of 3,974 patients survived beyond day 100 after transplant and their cumulative incidence of cGVHD was 43.2% at day 500 and 44.9% at day 2,000 post-transplant. The cumulative incidence of extensive cGVHD was 28.8% at day 2,000 post-transplant. In multivariate analysis, variables predicting cGVHD were recipient age (p=0.000), donor age (p=0.002), diagnosis of hematological malignancy (HR=1.99, p=0.000), HLA class I mismatch by either serology or DNA typing (HR=1.24, p=0.020), acute GVHD (I: HR=1.50, p=0.000; II: HR=2.07, p=0.000; III and IV: HR=2.25, p=0.000) and no platelet recovery over 50,000/mm3 before day 100 (HR=1.36, P=0.002). There was a significant difference between patients <20 and ≥20 years old (HR=1.27, p=0.000). However, there were no significant differences between any adults grouped by age decade (p=0.894). OS at 5 years in patients surviving >100 days post-transplant was 62.4% without cGVHD, 68.0% with limited cGVHD, and 55.4% with extensive cGVHD (p=0.000). In the patients with hematological malignancies, OS at 5 years was 58.8%, 67.3% and 55.8%, respectively (p=0.000). Cumulative incidence of relapse of hematological malignancies at day 2,000 in patients surviving >100 days post-transplant was 17.6% with limited cGVHD, 18.4% with extensive cGVHD and 27.1% without cGVHD (P=0.000). Conclusions: This study provides strong evidence of risk factors for developing cGVHD after UR-BMT and suggests that limited cGVHD provides a survival benefit to patients with hematological malignancies by reducing the risk of relapse without increasing the risk of death from cGVHD. There was a significant difference in occurrence of cGVHD between patients <20 and ≥20 years old but no differences comparing any age ≥20 years.

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Second Malignancies After Autologous Hematopoietic Cell Transplantation (AHCT) for Multiple Myeloma (MM): A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis

Blood ◽

10.1182/blood.v120.21.591.591 ◽

2012 ◽

Vol 120 (21) ◽

pp. 591-591

Author(s):

Girindra Raval ◽

Anuj Mahindra ◽

Xiaobo Zhong ◽

Ruta Brazauskas ◽

Robert Peter Gale ◽

...

Keyword(s):

Risk Factors ◽

At Risk ◽

Multivariate Analysis ◽

General Population ◽

Cumulative Incidence ◽

Incidence Rates ◽

High Dose ◽

Risk Of Death ◽

Age And Sex

Abstract Abstract 591 Background: Survival of patients with MM has improved over the past two decades, in part due to the use of AHCT. Increasingly, second primary malignancies (SPMs) are observed in MM survivors. Determining the baseline incidence and risk factors associated with SPMs after AHCT is important to assess risk and to evaluate the risk-benefit ratio of newer therapies. Methods: We analyzed the incidence of SPMs in 3784 MM patients receiving (“upfront”) AHCT for MM within 18 months of diagnosis between 1990 and 2010 and reported to the CIBMTR. Cumulative incidence rates of SPMs were estimated taking into account the competing risk of death. For each transplant recipient, the number of person-years at risk was calculated from the date of transplantation until date of last contact, death, or diagnosis of SPM, whichever occurred first. Incidence rates for all invasive cancers in the general population were obtained from the SEER database. Age-, sex-, and race- specific incidence rates for overall SPMs and particular anatomical sites were applied to the appropriate person-years at risk to compute the expected numbers of cancers. Observed–to –expected (O/E) ratios were calculated, and Poisson distribution 99% confidence intervals (CIs) were generated. Poisson regression model was used to analyze risk factors for overall SPMs and AML/MDS. Results: Pre-transplant therapy included novel agents in 56% including thalidomide (35%), lenalidomide (9%), bortezomib (16%) or their combinations (11%). Majority (80%) received high dose melphalan conditioning. Post-transplant maintenance therapy included thalidomide (16%), lenalidomide (8%), bortezomib (9%) and interferon (6%). Median follow-up of survivors was 52 months (range 3 to 192 months).With 12707 person years of follow up, 153 new malignancies were reported with a crude rate of 1.2 SPM per 100 person years of follow up. Observed/Expected [O/E] ratio for all SPMs was 0.99 (99% CI, 0.80–1.22). Cumulative incidence of SPM overall was 2.48% (95% CI, 1.96–3.05) at 3 years and 6.0% (95% CI, 4.96–7.10) at 7 years [Figure 1]. Individual SPMs observed significantly more frequently than expected are summarized in Table 1. The cumulative incidence of MDS/AML was 0.5% (95% CI, 0.28–0.78) at 3 years and 1.3 (95% CI, 0.85– 1.9%) at 7 years. Majority had MM progression prior to diagnosis of SPM (65 of 102 patients overall and 15 of 23 patients for MDS/AML). In multivariate analysis, significant risk factors for development of SPMs included: obesity [Hazard ratio = HR 1.89(95%CI, 1.21–2.93), p=0.0047 for BMI>30 vs. BMI<25], older age: [HR10.53 (95%CI, 1.46–75.82), p=0.0195] for 60–69 year olds and HR14.4 (95%CI, 1.89–109.75), p=0.01 for 70+ year olds compared to the 18–39 year old group. Specific conditioning regimens did not correlate with the risk of SPM. The low number of MDS/AML (33 events out of 3784 cases) limited the power of multivariate analysis. Increasing age was significantly associated with development of MDS (HR10.77, (95%CI,92.09–55.51), p=0.004 for 70+ year old vs. 40–49 year olds). Conclusion: In this large cohort of AHCT recipients for MM, the incidence of MDS/AML, melanoma and other skin cancers was significantly higher compared to age and sex matched general population. However the overall risk of SPM was similar to that expected for age and sex matched population. It was also similar to the placebo arms of recent reports by McCarthy Pl et al and Attal M et al (N Engl J Med. 10; 366(19):1770–91). Lenalidomide (8%) or thalidomide maintenance (16%) used in a small subset of patients with comparatively short follow up, was not associated with risk of SPM in the analysis of the overall cohort. Disclosures: Gale: Celgene: Employment. Brandenburg:Celgene: Employment, Equity Ownership. Lonial:Millennium, Celgene, Novartis, BMS, Onyx, Merck all Consultancy. Krishnan:Celgene and Millennium: Consultancy, Speakers Bureau. Dispenzieri:Celgene and Millennium: Research Funding. Hari:Celgene: Consultancy, Honoraria.

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Encoraging Results after Alternative Donor Transplantation for Myelodysplastic Syndrome.

Blood ◽

10.1182/blood.v112.11.1964.1964 ◽

2008 ◽

Vol 112 (11) ◽

pp. 1964-1964

Author(s):

Franco Locatelli ◽

Adrienne Moreno-Madureira ◽

Pierre Teira ◽

Mary Eapen ◽

Mei-Jie Zhang ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Marrow Transplant ◽

Hematopoietic Stem ◽

Monosomy 7 ◽

Neutrophil Recovery ◽

Blood And Marrow Transplant

Abstract Hematopoietic stem cell transplantation (HSCT) remains the treatment of choice for children with myelodysplastic syndromes (MDS). Umbilical cord blood (UCB) represents an alternative source of hematopoietic stem cells for transplantation in children without a HLA-matched sibling. We examined risk factors influencing outcomes after UCB transplantation (UCBT) in 70 children (40 males and 30 females; median age 7 years, range 0.8–18) with MDS reported to the European Working Group of MDS in Childhood, the Center for International Blood and Marrow Transplant Research or the Eurocord-European Blood and Marrow Transplant Group. Excluded were patients who had received prior autologous/allogeneic HSCT and those with Down syndrome, Fanconi anemia, or MDS that evolved to AML prior to HSCT. Patients had refractory cytopenia (RC, n=31), refractory anemia with excess blasts (RAEB, n=30), and RAEB in transformation (RAEB-t, n=9). All patients received a single UCB unit and myeloablative preparatory regimen. Karyotype analysis (available for 68 of 70 patients) was normal in 22 patients, while the remaining 46 had cytogenetic abnormalities, the most frequent being monosomy 7 (n= 23). In all pairs but one, donor-recipient histocompatibility was determined by serology (low-resolution typing) for HLA-A and -B and allele-level typing for DRB1. UCB units were HLA matched (A, B, DRB1) in 4 cases, 1-locus, 2-loci and 3-loci mismatched in 34, 26 and 5 cases, respectively. The day-60 probability of neutrophil recovery was 76%; in multivariate analysis, transplantation of HLA matched or 1-locus mismatched UCB, irradiation-containing preparatory regimen, cell dose ≥ 6x107/kg (pre-cryopreservation) and monosomy 7 were associated with faster neutrophil recovery. The 100-day probability of grade II-IV acute graft-versus-host disease (GVHD) was 30% (95% CI, 20–41). The 3-year cumulative incidence of chronic GVHD was 23% (95%CI 14–33). Five of 16 patients with chronic GVHD had limited and 11 extensive chronic GVHD. Twenty-nine patients died from transplantation-related complications, the 3-year cumulative incidence of transplantation-related mortality (TRM) was 41% (95% CI 29–52). Three deaths were related to GVHD. In multivariate analysis, TRM was lower when transplants were performed after 2001 (HR 0.41, 95%CI 0.20–0.84, p=0.015). Thirteen patients had recurrent disease and 11 were dead at last follow up. No variable predicted disease recurrence. With a medium follow-up of 39 months (range 10 – 105), the 3-year probability of disease-free survival (DFS) for the entire cohort was 39%; it was 50% when transplantation was performed after 2001 compared to 27% in the earlier period (p=0.02). After 2001, patients received UCB containing higher cell doses and the interval from diagnosis to transplantation was shorter. The 3-year DFS was 61% for the 23 patients with monosomy 7 compared to 30% for patients with other karyotypes (p=0.042). In multivariate analysis, year of transplantation (prior to 2001) and cytogenetic abnormalities other than monosomy 7 were independent risk factors predicting treatment failure, HR 2.38, (95% CI: 1.14–5.0, p=0.02) and HR 2.04,(95% CI: 1.11–3.70, p=0.02), respectively. The 3-year DFS was not influenced by MDS variant. Given the relatively small sample size the influence of MDS variant on transplant-outcome requires validation in a larger series. These data indicate that UCBT is an acceptable alternative in children with MDS without a HLA-matched related or unrelated adult bone marrow donor. The results of UCBT have improved in recent years and monosomy 7 does not confer an unfavourable outcome.

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Risk Factors for Major Transplant Related Outcomes In Pediatric Patients with Chronic Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v116.21.211.211 ◽

2010 ◽

Vol 116 (21) ◽

pp. 211-211

Author(s):

David A. Jacobsohn ◽

Mukta Arora ◽

John P. Klein ◽

Joseph H. Antin ◽

Brian J. Bolwell ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Blood Cell ◽

Immune Suppression ◽

Peripheral Blood ◽

Cumulative Incidence ◽

Conflicts Of Interest ◽

Chronic Gvhd ◽

Peripheral Blood Cell ◽

Myelogenous Leukemia

Abstract Abstract 211 The adverse impact of chronic GVHD (cGvHD) on health and quality of life is especially critical in children because of their longer life expectancy and problems impacting growth and development. Although risk-factors for developing cGvHD in children are reported, little is known about risk factors for non-relapse mortality (NRM) in children with cGvHD. Identification of predictors for mortality in children with cGvHD could permit risk-adapted therapy, help plan for clinical trials and assist in counseling. We performed a multivariate analysis using data from CIBMTR to identify transplant- and cGvHD-related risk factors for NRM and survival in a cohort of 1117 subjects aged 0–20 years, transplanted from related donors, unrelated donors (URD), or unrelated cord blood (UCB) in 1995–2004 for acute myelogenous leukemia (AML), acute lymphoid leukemia (ALL), chronic myelogenous leukemia (CML) or myelodysplastic syndrome (MDS). Median age was 12 years. Characteristics of cGvHD at diagnosis were: progressive onset (49%), total bilirubin >2 mg/dL (16%), thrombocytopenia (platelets <100 × 109/L, 32%) and Karnofsky/Lansky (KPS/L) score <80 (24%). Probabilities of NRM at 1, 3, and 5 years after diagnosis of cGvHD were 17% (95% CI: 14–19%), 22% (20-25%) and 24% (21-27%), respectively. Multivariate analysis indentified four factors significantly associated (p<0.01) with higher NRM: (1) HLA-partially-matched or -mismatched URD; (2) peripheral blood cell graft; (3) KPS/L <80 at cGVHD diagnosis; and (4) platelets <100 × 109/L at cGVHD diagnosis. Survival after diagnosis of cGVHD at 1-, 3- and 5-years was 75% (72-77%), 63% (60-66%), and 59% (56-62%). Factors significantly associated with worse survival were: (1) age >10 years; (2) transplant from an HLA-partially-matched or -mismatched URD; (3) advanced disease at transplant; (4) KPS/L <80; and (5) platelets <100 × 109/L. The cumulative incidence of NRM at 5 years was higher for children with KPS/L <80 (46%; CI: 40–52%) than for those with a higher KPS/L score (15%; CI: 12–18%; p<0.001). This translated to poorer survival of 42% (36-48%) vs. 66% (CI: 63–70%; p<0.001), respectively. 5 year cumulative incidence of NRM was also higher in children with platelets <100 × 109/L: 37% (32-43%) vs. 15% (CI: 12–18%; p<0.001). This also resulted in poorer survival (47%, CI: 42–52%; vs. 67%, CI: 63–71%; p<0.001). Cumulative incidence of discontinuation of systemic immune suppression (death and relapse treated as competing risks) at 1, 3 and 5 years after diagnosis of cGvHD were 22% (20-25%), 34% (31-37%), and 37% (34-40%). In conclusion, we identified several factors adversely correlated with NRM and survival children with cGvHD. The correlation between peripheral blood cell grafts and increased NRM without poorer survival may be explained by fewer relapses. This is the first large study elucidating factors affecting outcome after diagnosis of cGvHD in children. Our results may be useful for risk stratification.SurvivalNRMRelative Risk95% CIPRelative Risk95% CIPAge (baseline: 0–9 years) 10-191.321.091.600.005NSKPS/L (baseline: 80–100)<.001<.001 <801.891.522.34<.0013.012.293.96<.001 unknown1.341.001.780.051.641.122.430.015Platelets (x10e9/L) (baseline: ≥ 100)<.001<.001 <1001.631.322.01<0.0012.321.763.07<.001 Unknown1.330.991.780.061.731.182.520.005Donor (baseline: HLA-identical siblings)0.003<0.001 Other related1.681.132.520.0111.670.962.960.07 HLA-well-matchedunrelated1.401.021.940.041.250.801.960.33 Partially matched unrelated1.691.232.310.0011.941.282.940.002 Mismatched unrelated1.751.272.42<0.0012.311.493.59<0.001No data1.020.641.620.941.220.602.130.71Disease State (baseline: Early)<0.0010.005 Intermediate0.960.781.180.700.650.500.850.07 Advanced1.561.192.040.0010.920.631.350.68Graft (baseline: BM)0.002 BloodNS1.761.282.41<0.001 Cord BloodNS1.070.671.700.78NS=Not SignificantCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDCumulative Incidence of NRM by Platelets and KPS/L at Diagnosis of cGvHDSurvival and Cumulative Incidence of Discontinuation of Immune SuppressionSurvival and Cumulative Incidence of Discontinuation of Immune Suppression Disclosures: No relevant conflicts of interest to declare.

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Superior Outcome Using Cyclosporin A Alone Versus Cyclosporin A Plus Methotrexate for Post-Transplant Immunosuppression In Children with Acute Leukemia Undergoing Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v116.21.4502.4502 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4502-4502

Author(s):

Bernd Gruhn ◽

Melissa Weiß ◽

Ilona Wolff ◽

Felix Zintl ◽

James F. Beck

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Cyclosporin A ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Hematopoietic Stem ◽

Post Transplant ◽

Graft Versus Leukemia ◽

Significant Difference ◽

Graft Versus Leukemia Effect

Abstract Abstract 4502 Graft-versus-host disease (GVHD) is a major complication and one of the main causes of death after hematopoietic stem cell transplantation (HSCT). The GVHD prophylaxis influences the incidence of GVHD, relapse rate, and patient's survival. GVHD is associated with graft-versus-leukemia effect, which is mediated by donor T lymphocytes and decreases the risk of relapse. Therefore, a reduced post-transplant immunosuppression might have a positive impact on patient's survival. The outcome of different immunosuppressive prophylaxis regimen for adult patients has been studied extensively, whereas the effect on children has yet to be determined. Therefore, we performed a retrospective study analyzing 62 children (median age, 11 years) with acute lymphoblastic leukemia (n=35) or acute myeloid leukemia (n=27) who underwent bone marrow (n=56), peripheral blood stem cell (n=4), or umbilical cord blood (n=2) transplantation in a single center between November 1984 and July 2008. All respective donors were HLA-identical siblings. The patients received an immunosuppressive prophylaxis consisting of cyclosporin A (CSA) plus methotrexate (MTX) (n=43) or cyclosporin A alone (n=19). Patients in the CSA+MTX arm received CSA at a total dose of 10 mg/kg/day on day -1, 5mg/kg/day on days 0 to 4, and 3 mg/kg/day starting on day 5, and in addition MTX at a dosage of 10 mg/m2 on days 1, 3, 6, and 11. The 19 patients in the CSA arm received CSA at a total dose of 3 mg/kg/day starting on day -1. Concerning the patient's gender, age, diagnosis, and state of remission prior to transplantation, the two groups did not differ significantly. Patients who received CSA alone as post-transplant immunosuppression had a significantly reduced cumulative incidence of relapse (5% versus 40%; p=0,002), a significantly increased 5-year event-free survival (84% versus 35%; p=0.001), and a significantly increased 5-year overall survival (84% versus 42%; p=0.004). Interestingly, the incidence of acute GVHD grade II-IV in patients in the CSA arm was equivalent to the CSA+MTX arm (26% versus 19%; p=0.440). In addition, we did not observe a significant difference in the cumulative incidence of chronic GVHD (32% in the CSA arm versus 23% in the CSA+MTX arm; p=0.428). There was also no significant difference in the cumulative incidence of treatment related mortality after 1 year (10% in the CSA arm versus 23% in the CSA+MTX arm; p=0.165). In conclusion, CSA alone for post-transplant immunosuppression allows a stronger graft-versus-leukemia effect and thereby reduces the relapse rate and the number of patients dying of leukemia effectively without increase of acute and chronic GVHD. Post-transplant immunosuppression consisting of CSA alone leads to a superior outcome and should be preferred in children with a HLA-identical sibling as donor. Disclosures: No relevant conflicts of interest to declare.

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Outpatient Haploidentical Peripheral Blood Stem-Cell Transplantation with Post-Transplant Cyclophosphamide in Children and Adolescents

Blood ◽

10.1182/blood.v126.23.4389.4389 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4389-4389

Author(s):

Oscar Gonzalez-Llano ◽

Elias Eugenio Gonzalez-Lopez ◽

Ana Carolina Ramirez-Cazares ◽

Edson Rene Marcos-Ramirez ◽

Guillermo J. Ruiz-Arguelles ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

High Risk ◽

Children And Adolescents ◽

Hematological Malignancies ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Dose ◽

Post Transplant

Abstract Patients with high-risk hematological malignancies have a poor prognosis without a hematopoietic stem cell transplant. An HLA- haploidentical donor is available in 95% of the cases, and post-transplant cyclophosphamide permits the use of T-cell replete grafts in settings were ex-vivo manipulation is not available. The experience with HLA-haploidentical HSCT with PBSC and post-tranplant Cy in the pediatric and adolescent population is limited; we report the following experience. We retrospectively collected data on 25 patients (0 to 21 years old) with hematological malignancies, who underwent ambulatory haploidentical HSCT with post-transplant Cy from November 2011 to November 2014. The different conditioning regimens are described in Table 1. All patients received high-dose Cy(50mg/kg) on days +3 and +4. Cyclosporine A (CYA; 6mg/kg/d per os) and mycophenolate mofetil (MMF; 15mg/kg two times daily per os) were started on day +5. MMF was discontinued on day +35 and tapering of cyclosporin started day +90 in the absence of GVHD. All patients received anti-microbial prophylaxis for bacteria, fungal, herpes infection and Pneumocystis jiroveci according to institutional practices. First chimerism was performed at day +30, and second chimerism at day +100. Primary graft failure was defined when neutrophil counts did not exceed 0.5 x 109/L by day +30. Acute and chronic GVHD were graded according to NIH criteria. Patient, donor and stem-cell harvest characteristics are described in Table 1. All patients had high risk hematological malignancies. There were 5 patients who underwent their first transplant on 1st CR, 4 with ALL with high risk cytogenetics and 1 with AML. All other patients were defined as high risk because they were refractory/relapsed. Twenty-three patients (92%) had neutrophil engraftment after a median 17 (7-24) days. Platelet engraftment was observed in 20 (80%) patients after a median of 14.5 (11-23) days, 3 (12%) patients did not have platelet counts below 20,000/mcL. One patient was catalogued as a primary failure for not achieving neutrophil and platelet engraftment by day +30. One patient died before engraftment at day +10 of septic shock. Four patients (16%) died before day +30. The only patient that did not have a complete chimerism, had a diagnosis of AML and 30% of donor cells by day +30, by day +45 relapse of disease was documented. After a median follow-up of 157 days, 13 patients (52%) remain alive, with an estimated 1-year OS of 52% (95%CI: 30.4 - 65.6%).Nine patients (36%) died of complications (mainly infectious) not related to relapse at a median time of 66 days (10-579 days) from stem cell infusion. Nine patients (36%) relapsed in a median time of 105 days (45-288 days); three of those patients died at days +150, +113 and + 370 from transplant. Estimated 1 year event-free survival is 40.2% (95%CI: 41.3 - 75.8%) (Figures 1 and 2). Patients transplanted on 1st CR had a median follow-up of 664 days with an OS and EFS of 80% (4 patients), which was statistically different from the rest of the population (p=0.03) (Figure 3). Among those who engrafted (n=21), 9 cases (42.9%) had grade 2-4 acute GVHD and 4 cases (19%) of grade 3-4 acute GVHD. Three patients (14.3%) developed chronic GVHD, two had mild skin or liver cGVHD. One patient had severe (NIH stage 3) skin cGVHD, she was alive and with a grade 2 cGVHD until last follow up at day +893. Outpatient procedure, HLA-haploidentical HSCT including PBSC as a stem cell source, and post-transplant T-cell in vivo depletion using high-dose cyclophosphamide is feasible in children and adolescents, with acceptable rates of response and GVHD. Table 1. Patient, donor and harvest characteristics Variable N=25 Age, median(range in years) 10 (1-21) Gender, n(%) Male Female 17 (68%) 8 (32%) Diagnosis, n(%) ALL-B ALL-T AML CML 16 (64%) 2 (8%) 5 (20%) 2 (8%) Time from diagnosis to transplant (months) 17.2 (1.9-153.5) Conditioning regimen, n(%) Cy 1500mg/m2 + Flu 75mg/m2 + Bu 9.6mg/kg (IV) Cy 1050mg/m2 + Flu 75mg/m2 + Bu 12 mg/kg (oral) Cy/VP-16/RT Cy/Flu/Mel 16 (64%) 6 (24%) 2 (8%) 1 (4%) Donor, n(%) Mother Father Sister 20 (80%) 3 (12%) 2 (8%) Donor age, median(range in years) 38 (17-49) Infused CD34+ x 106/kg, median(range) 11 (3.2-20) Disclosures No relevant conflicts of interest to declare.

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Hyperlipidemia After Allogeneic Stem Cell Transplantation: Prevalence, Risk Factors and Impact on Prognosis.

Blood ◽

10.1182/blood.v116.21.3458.3458 ◽

2010 ◽

Vol 116 (21) ◽

pp. 3458-3458

Author(s):

Yuki Kagoya ◽

Sachiko Seo ◽

Yasuhito Nannya ◽

Mineo Kurokawa

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Relapse Rate ◽

Allogeneic Stem Cell Transplantation ◽

Cumulative Incidence ◽

Chronic Gvhd ◽

Calcineurin Inhibitors

Abstract Abstract 3458 Introduction: Hyperlipidemia is one of the late complications after allogeneic stem cell transplantation (SCT). Although intrahepatic cholestasis caused by chronic graft-versus host disease (GVHD) or calcineurin inhibitors has been considered to be one of the etiologies, its prevalence, risk factors, and the impact on prognosis have not been investigated well. Methods: We performed a retrospective analysis of 194 adult patients who underwent allogeneic SCT between 1995 and 2008 in our institute, and survived more than 100 days after SCT. Hypercholesterolemia or hypertriglyceridemia was defined as more than 240 mg/dl or 200 mg/dl, respectively, at two successive tests at least one week apart after the first 100 days after SCT. Cumulative incidence of hypercholesterolemia or hypertriglyceridemia was analyzed. The time to the development of hypercholesterolemia or hypertriglyceridemia was calculated and the multivariate analysis of pre- and posttransplant variables was performed by a Cox proportional hazards model. Chonic GVHD, chronic liver dysfunction (CLD; defined as more than twice the upper limit of normal for aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase, or total bilirubin >3 mg/dl over 3 months) and administration of calcineurin inhibitors were studied as posttransplant factors, which were assessed as time-dependent variables. To analyze the prognosis of patients who developed persistent hyperlipidemia, the multivariate analysis of overall survival (OS), relapse rate, and non-relapse mortality (NRM) was carried out by a landmark approach. Persistent hyperlipidemia was defined as hypercholesterolemia or hypertriglyceridemia continuing more than 3 months. Results: Overall, 83 (42.8%) and 98 (50.5%) patients developed hypercholesterolemia and hypertriglyceridemia, respectively. The median follow-up period of serum cholesterol and triglyceride values in surviving patients was 44 months. The cumulative incidence of each abnormality at 3 years after SCT was 38.1% (95% confidence interval [CI]: 31.0–45.1%), and 46.0% (95% CI: 38.8–52.9%), respectively. In a multivariate analysis, the development of chronic GVHD was independently associated with both hypercholesterolemia (hazard ratio [HR] 2.05, 95% CI: 1.23–3.43, P<0.01) and hypertriglyceridemia (HR 2.04, 95% CI: 1.30–3.18, P<0.01). Besides, CLD was significantly associated with hypercholesterolemia (HR 2.20, 95% CI: 1.39–2.50, P<0.01). Administration of calcineurin inhibitors was not an independent risk factor for the development of hypercholesterolemia (HR 1.23, 95% CI: 0.73–2.08, P=0.43) or hypertriglyceridemia (HR 1.03, 95% CI: 0.61–1.54, P=0.89). Among pretransplant factors, prior hypercholesterolemia and hypertriglyceridemia were associated with posttransplant hypercholesterolemia (HR 2.76, 95% CI: 1.07–7.17, P=0.04) and hypertriglyceridemia (HR 2.04, 95% CI: 1.27–3.27, P<0.01), respectively. Persistent hyperlipidemia was found in 49 patients (25.3%), of which 35 patients (71.4%) developed hyperlipidemia within one year. The median interval to the occurrence of hyperlipidemia of the patients was 180 days after SCT. In univariate analysis, patients with persistent hyperlipidemia had a tendency of better 3-year OS (77.3% vs 64.7%, P=0.23). Multivariate analysis showed that the development of persistent hyperlipidemia was independently associated with better OS (HR: 0.49, P=0.049). Further, although not statistically significant, patients with persistent hyperlipidemia had a tendency of lower 3-year cumulative relapse rate (15.7% vs 20.3%). There were no significant differences in 3-year NRM between patients with or without hyperlipidemia (12.3% vs 13.9%). Conclusions: Both hypercholesterolemia and hypertriglyceridemia are very common complications after SCT. Patients with persistent hyperlipidemia, however, have significantly better OS. Considering a strong association between the development of hyperlipidemia and chronic GVHD, and a tendency of lower relapse rate in patients with persistent hyperlipidemia, hyperlipidemia is regarded as one of the symptoms accompanied with chronic GVHD. Unless severe, its incidence indicates a better control of the primary disease and an improved prognosis. Disclosures: No relevant conflicts of interest to declare.

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“CARDIOVASCULAR and Metabolic Complications in Patients with Hematological Malignancies Undergoing Allogeneic Hematopoietic STEM CELL Transplantation (HSCT)”

Blood ◽

10.1182/blood.v124.21.1149.1149 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1149-1149

Author(s):

Eleonora Arboscello ◽

Vera Sicbaldi ◽

Federica Galaverna ◽

Fabio Guolo ◽

Paolo Spallarossa ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Hematological Malignancies ◽

Older Age ◽

High Dose ◽

Reduced Intensity Conditioning ◽

Conditioning Regimens ◽

Long Term Survivors

Abstract Background: HSCT has greatly improved the prognosis of patients affected by hematological malignancies leading to more long-term survivors. However, long-term survivors are at increased risk of developing complications; cardiovascular complications are relatively rare but, on the other hand, it seems quite common to develop cardiovascular risk factors like: arterial hypertension (AH), diabetes, dyslipidemia. Aims of the study: to observe the incidence and outcome of patients developing cardiovascular risk factors (CVRF) and cardiovascular events (CVE) after allo-HSCT, eventually identifying patient and HSCT-related risk factors for CVE (CVE predictors). Materials and methods: We retrospectively analyzed 300 patients undergoing allo-HSCT from January 2006 to December 2009. Patients were considered long-term survivors and suitable for the analysis if they were alive at 2 years after HSCT. Following variables were recorded: diagnosis, sex, age at time of HSCT, comorbidities and pre-existing risk factors, BMI, previous chemotherapy with anthracyclines, donor type, disease status at time of HSCT, conditioning regimens with or without total body irradiation (TBI), onset of acute or chronic graft versus host disease (aGVHD and cGvHD), treatment with high doses corticosteroids after HSCT. We observed incidence and outcome of early (within 2 years) and late (after 2 years) CVRF and CVE in long-term survivors; CVE were divided in non-serious (grade1-2) and serious (grade 3-4) if they required or not hospitalization. Dichothomius variables were compared with Chi-Square test or Fisher's exact test. Continuous variables were compared with Student's T-Test. Median Follow-Up duration was estimated with Kaplan Meier reverse survival method. Multiple linear regression models were built for multivariate analysis of CVE incidence. A two-sided p value <0.05 (<0.02 for multivariate analysis) was considered statistically significant. Results: 4 of 300 patients died of acute heart failure within 2 years from HSCT. 149 patients were alive at least 2 years after HSCT, and 125 patients (83%) were alive at the time of last follow-up, with a median follow-up of 2384 days (range 722-3098) and a median age of 40 years (range 15-72). Overall crude mortality was 24/ 149 (17%), of whom 16 patients dying of disease recurrence (66%) and 8 patients (34%) dying due to non-relapse causes (Non Relapse Mortality, NRM). Non-serious CVE were observed in 42 patients (28%), whereas serious CVE were reported in 23 cases (15%; 5 acute coronary syndrome, 4 heart failure, 5 cardiac arrythmias, 5 cerebrovascular events, 2 aortic aneurism, 2 pericarditis), with 11 patients experiencing both. Regarding CVRF, post-HSCT AH was observed in 62 patients (42%), dyslipidemia in 124 pts (83%), diabetes in 29 pts (19%). In univariate analysis older age was associated with a higher risk of developing late diabetes (p 0.025), early and late AH (p<0.001), any CVE (p=0.04). cGVHD was associated with a higher risk of early AH (p 0.018), while aGVHD, advanced disease at HSCT and use of high dose of corticosteroids were associated with serious CVE (respectively p=0.039,p=0.025,p=<0.0001). In multivariate analysis, Event Free Survival (EFS) for any CVE was lower in case of older age (p=0.01), acute and chronic GvHD (p=0.010, p=0.006), pre-existing AH (p=0.001) and smoke abuse (p=0.01), reduced intensity conditioning regimens (p=0.03), and high dose corticosteroids treatment (p=0.001). Furthermore, serious CVE were associated with male sex, reduced intensity conditioning regimen, use of TBI within conditioning regimens, older age, and pre-existing AH (respectively p=0.006, p=0.026, p=0.002, p=0.009, p=0.038). Older age was also associated with the development of late AH (p=0.001) and late diabetes (p=0.025) Conclusions: Older allo-HSCT patients have an higher risk of developing any CVE and any CVRF than age-matched non-hematologic population; interestingly, prolonged treatment with high dose steroids also seems to play a role. CVE do not show nowadays a high impact on survival since they seems to be an uncommon complication of HSCT. Furthermore an increasing number of late CVRF has been observed, possibly leading to late cardiovascular events in the future and should therefore be monitored. Disclosures No relevant conflicts of interest to declare.

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Cardiac and Pulmonary Function Late Effects after Bone Marrow Transplantation in Childhood: Prospective Study on Behalf of EBMT LEWP Group.

Blood ◽

10.1182/blood.v106.11.1113.1113 ◽

2005 ◽

Vol 106 (11) ◽

pp. 1113-1113

Author(s):

Cornelio Uderzo ◽

Paola Corti ◽

Sara Fedeli ◽

Francesco Tana ◽

Chiara Messina ◽

...

Keyword(s):

Risk Factors ◽

Bone Marrow ◽

Multivariate Analysis ◽

Bone Marrow Transplantation ◽

Pulmonary Function ◽

Late Effects ◽

Cumulative Incidence ◽

Hazard Rate ◽

Conditioning Regimen

Abstract BACKGROUND Patients (pts) undergoing bone marrow transplantation (BMT) for hematological childhood disorders might present long-term cardiac and pulmonary function (CPF) complications. The current study assessed incidence and risk factors of CPF late sequelae by a multicenter study. METHODS From March 1994 to December 1997 we enrolled 220 consecutive children (130 males, median age at BMT 9,5 yrs) who underwent BMT (162 allogeneic and 58 autologous) for malignant (193) and non malignant (27) diseases in 9 EBMT centers. Total body irradiation (TBI) based conditioning regimen was used in 120/220 pts. A total of 165/220 pts were alive at the end of the study with a reliable CPF assessment which consisted of pulmonary function tests (PFTs) and M-Mode echocardiography performed at pre-BMT phase, at 1st year post-BMT and yearly. Statistical analysis to evaluate the difference between pre-BMT and post-BMT CPF was performed by paired t-test, while the assessment of risk factors was based on univariate and multivariate analysis. RESULTS Median follow-up of evaluable pts was 5 yrs (range 4–8 yrs). Fifty-five of 220 patients deceased, none for late CPF abnormalities. The 5-year cumulative incidence of lung and cardiac impairment was 35% (hazard rate=0,07) and 23% (hazard rate =0,04) respectively. Patients presenting abnormal PFTs and shortening fraction (SF) at last follow-up were 15% and 12% respectively, even if asymptomatic. Chronic GVHD was a major risk factor in reducing lung function at both univariate (P=0.02) and multivariate analysis (P=0,006). Patients undergoing TBI based conditioning regimen showed a SF impairment at multivariate analysis (P=0,03). Gender, age, diagnosis, pre-BMT anthracyclines, BMT type, non-TBI based conditioning, malignant or non malignant diseases at BMT were not significantly related to pulmonary and cardiac late effects. No difference was ascertained in the cumulative incidence of non relapse mortality in a competing risk setting which suggests that BMT can also be successful for those children who experienced both abnormal PFTs and SF. At the end of the study all surviving pts had a median Lansky index >90. CONCLUSIONS Our study focused on low incidence of only asymptomatic CPF late effects in children transplanted for hematological disorders. TBI for cardiac function and C-GVHD for pulmonary function are the most important risk factors. Despite most of the alive pts remains in the normal range both for CPF complications from the beginning of BMT up to 5th year of median follow-up, a continue surveillance at least in adolescent age is recommended.

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Prevention of Graft-Versus-Host Disease (GVHD) with Tacrolimus after Allogeneic Grafting for Hematological Malignancies Following Sub-Myeloablative Conditioning.

Blood ◽

10.1182/blood.v108.11.5321.5321 ◽

2006 ◽

Vol 108 (11) ◽

pp. 5321-5321

Author(s):

Joseph Fay ◽

Giovanna Saracino ◽

Edward Agura ◽

Brian Berryman ◽

Luis Pineiro ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Hematological Malignancies ◽

Chronic Gvhd ◽

Progression Free Survival ◽

P Value ◽

Hematopoietic Stem ◽

Free Survival ◽

Allogeneic Hsct ◽

Post Transplant

Abstract Severe acute or chronic GVHD following allogeneic hematopoietic stem cell transplantation therapy (HSCT) has a deleterious effect on the successful treatment of hematological malignancies. We have retrospectively studied mycophenolate mofetil (MMF) and tacrolimus (FK) or cyclosporine (CSA) following allogeneic HCST in the prevention of GVDH and the induction of immune tolerance in 93 patients with hematological malignancies using non-myeolablative pre-transplant conditioning. In the current study, there were 35 patients with leukemia, 36 patients with lymphoma, 12 patients with myelodysplastic syndrome or a myeloproliferative disorder and 10 patients with multiple myeloma. There were 63 women and the median age was 42 (15–75) years. Twenty patients had relapsed after previous autologous or allogeneic HSCT and 45 patients were older than 59 years. The remaining patients had co-morbid medical conditions that precluded the use of chemotherapy/radiotherapy dose-intensive pre-conditioning. Conditioning prior to allogeneic HSCT (94 blood stem cell grafts and 1 marrow graft) was fludarabine (90 mg/m2 in three daily doses) and TBI (200cGy) in 86 patients, fludarabine (120 mg/m2 in 4 daily doses) and cyclophosphamide (50mg/kg) in 5 patients, and TBI (200 cGy) only in 4 patients. Forty-three patients received sibling and 50 unrelated grafts. Median follow-up post transplant is 3.0 (0.2–6.1) years. Five (5.3%) patients did not experience sustained hematological chimerism post-transplant. MMF and FK were administered to 33 recipients and MMF and CSA to 60 recipients. The dose and schedule of MMF, CSA and FK have been published (Laport et al. Blood, 2006 and Fay et al. Blood, 1996.) There was no difference in the degree of HLA mismatching between the two groups of patients. Cumulative incidences were used to estimate the incidence of acute and chronic GVHD, all deaths and disease progressions not related to GVHD being considered as the competing events. The Gray test was used to compare cumulative incidences between groups. The unadjusted cumulative incidence of grade III–IV acute GVHD that required oral or systemic corticosteroid therapy, was 54% (95% CI, 40%–68%) in evaluable patients who received CSA in contrast to 38% (95% CI, 18%–58%) in patients who received FK (p-value=0.25). Furthermore, the unadjusted cumulative incidence of extensive chronic GVHD at 1 year was 45% (95% CI, 32%–58%) for CSA versus 34% (95% CI, 14%–54%) for FK (p-value=0.48). Progression-free survival between patients who received FK or CSA at the time of the analysis of this study is similar (p-value=0.6191). The progression-free survival at 1 year was 43% (95% confidence interval [CI], 24%–62%) for CSA versus 43% (95% CI, 31%–55%) for FK. Analyses of the overall morbidity and the incidence of infectious complications between the 2 groups are ongoing. FK combined with MMF may be superior to CSA and MMF in the prevention of GVHD post sub-myeloablative allogeneic HSCT therapy for hematological malignancies and FK may result in improvement of treatment outcome. We believe further study is warranted.

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Two-Year Surveillance Study of Nosocomial Infections in Patients with Hematological Malignancies: Risk Factors for Antimicrobial Resistance and Their Impact in Mortality

Blood ◽

10.1182/blood.v128.22.4892.4892 ◽

2016 ◽

Vol 128 (22) ◽

pp. 4892-4892

Author(s):

Zoi Bousiou ◽

Antonia Syrigou ◽

Chrysavgi Lalayianni ◽

Christos Smias ◽

Ioanna Sakellari ◽

...

Keyword(s):

Risk Factors ◽

Multivariate Analysis ◽

Antimicrobial Resistance ◽

Hematological Malignancies ◽

Resistant Bacteria ◽

Surveillance Culture ◽

Safety Measures ◽

Infectious Episode ◽

Post Transplant ◽

The Impact

Abstract Background: Infections are a leading cause of morbidity and mortality in patients suffering from hematological malignancies, with resistant bacteria being a major contributor. Special precaution is needed in these patients due to immunosuppression and safety measures are warranted to reduce related complications. Surveillance studies can offer a better understanding of risk factors associated with resistant strains and mortality. Materials and Methods: All patients hospitalized in our department of hematology, hematopoietic stem cell transplantation (HSCT) and post-transplant unit during 2014 and 2015 who presented an infectious episode were included in our study. An infectious episode was defined as a clinically detected infection not necessarily associated with specific bacteria or a positive surveillance culture. A retrospective epidemiological study was conducted using clinical data and positive cultures along with information about resistance. Our goal was to explore risk factors for infections by resistant bacteria and examine the impact of resistance on mortality. Results: During the two-year period, we identified 439 infectious episodes, 55.4% deriving from the department of hematology and 44.6% from the HSCT and post-transplant unit. Hematological malignancy was diagnosed in 429 patients, with 62.2% suffering from acute leukemia. Prevalence of resistant bacteria in our study population was 37.1%, more frequently isolated in the HSCT and post-transplant unit (52.2% vs 34.7%, p=0.001). Most of them were gram-negative, with the main representative being KPC klebsiella pneumoniae (38.7%), followed by pseudomonas aeruginosa (17.2%). Gram-positive species accounted for 19% of resistant bacteria, including MRSA staphylococcus and VRE enterococcus species. During the first semester of 2014, we identified a burkholderia cepacia outbreak with a total of 13 cases, that was successfully handled and the microorganism was eradicated. Possible risk factors for the isolation of resistant bacteria were examined. Factors included in our analysis were diagnosis, department of hospitalization, transplantation, prior chemotherapy, the presence of central venous catheter (CVC) and the presence of neutropenia. In multivariate analysis, the only significant risk factor associated with isolation of resistant bacteria was the department of hospitalization (OR 2.57, CI 1.31-5.02, p= 0.006). Duration of neutropenia was not correlated with increased rates of antimicrobial resistance (p=0.91). Mortality rate was 5.2%, mostly related to infection. Of the 23 patients that died, only six deaths were attributed to refractory disease. However, from the remaining 17, we identified 7 who presented severe immunosuppression after transplantation due to graft versus host disease (GVHD). Mortality was increased in patients with isolation of a resistant strain (73.9% vs 26.1%, p=0.001) but was not related to resistant disease or in combination with GVHD (52.9% vs 50%, p= 0.9). Using multivariate analysis, significant factors predicting mortality were neutropenia, the presence of resistant bacteria and presence of CVC. Other factors included in our analysis were the department of hospitalization, transplantation, diagnosis and preceding chemotherapy. The most powerful factor was the isolation of resistant bacteria (OR 4.08, CI 1.48-11.25, p=0.006) followed by the presence of CVC (OR 3.78, CI 1.14-12.54, p=0.03). Finally, we compared the impact of resistant bacteria between 2014 and 2015 and we observed a significant reduction in 2015 (57.1% vs 33.9%, p<0.001). We assume that this reduction is the result of more robust safety measures, including isolation of contaminated patients, intensive surveillance cultures in all patients that were routinely hospitalized and personnel discipline according to the guidelines. Conclusion: From our study we can conclude that patient colonization and possibly personnel behavior play a significant role in spreading of resistant bacteria, as the department of hospitalization was the only significant factor of bacteria isolation. Our two departments are localized in different floors of the same building with different staff on each floor, which makes cross contamination difficult. Resistance has a major impact on mortality, but appropriate measures can change distribution and improve survival in patients with hematological malignancies. Disclosures No relevant conflicts of interest to declare.

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